The present invention relates to a polyunsaturated fatty acid-containing composition which may be formulated as a dietary supplement or a pharmaceutical preparation, and to the use of such composition for treating hypertriglyceridemia.
Several publications are referenced in this application by author name and year of journal publication in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
It is known that hyperlipidemia is a significant risk factor in the development of cardiovascular disease (CVD). Hyperlipidemia is a condition marked by an increase in serum levels of one or both of serum cholesterol and neutral fats, primarily triglycerides (TG). Research conducted over the last several decades has established that elevated serum TG levels constitute an independent risk factor for CVD. Accordingly, the development of agents for reducing or controlling serum TG levels has received considerable attention as a means of preventing or delaying the onset of CVD.
As a dietary treatment for hypertriglyceridemia, polyunsaturated fatty acids (PUFAs) have been recommended, in conjunction with limited caloric intake. In this connection, dietary marine oils have been shown to exhibit very potent hypotriglyceridemic (TG lowering) properties, especially in type V hypertriglyceridemic individuals (Roche, 1999; Harris 1999; Harris 1989).
Numerous studies have now shown that the daily consumption of fish oils containing as little as 2-4 grams of n-3 PUFAs can significantly decrease circulating TG levels in both normolipidemic and hypertriglyceridemic individuals (Harris 1989; Harris 1997). Although there has been some question regarding the constituent(s) of dietary marine oils that is (are) responsible for this hypotriglyceridemic effect, both eicosapentaenoic acid (20:5 n-3) (EPA) and docosahexaenoic acid (22:6 n-3) (DHA), which are major constituents of fish oils, have been shown to possess this hypotriglyceridemic activity in humans (Weber 1999; Agren, 1996). However, this effect is not a general attribute of the n-3 PUFAs, as oils containing dietary alpha-linolenic acid (18:3 n-3) (ALA), a precursor of EPA and DHA, have little if any hypotriglyceridemic activity even when consumed in oils delivering as much as 20 grams of ALA per day (Kelley 1993; Abbey, 1990). A hypotriglyceridemic effect has been reported for ALA-containing oils when consumed at extremely elevated concentrations (40-60 grams ALA/day) (Singer, 1990), but this effect compares poorly to that of dietary marine oils and may be a generalized effect of high doses of dietary PUFAs, since high doses of linoleic acid have similar properties. However, the dietary use of marine oils as hypotriglyceridemic agents is undesirable for many individuals due to their generally unpleasant taste and odor. Furthermore, many studies investigating the potential benefits of marine oil consumption report associated gastrointestinal problems such as bloating and gas.
There have been few reports on studies in humans to determine the extent to which consumption of stearidonic acid (SDA) influence in vivo conversion to longer chain fatty acids, i.e., Arachidonic acid and Docosapentaenoic acid (DPA). Those that have been published appear inconclusive. For example, no increase in longer chain n-3 fatty acids was seen in test subjects who consumed the daily dose of 0.65 g ALA and 0.17 g SDA (Wu, 1999). Intensive care unit patients who were administered the equivalent of 5.7 g ALA and 0.7 g SDA per day were found to have a 20% increase in the EPA content of red blood cell membranes that was statistically significant (Diboune, 1992). Measurement of plasma fatty acids in a similar group of patients showed a significant increase in DPA; however, there is no mention of the plasma content of the of EPA (Diboune, 1993).
Another fatty acid that can be found in some less common dietary oils is gamma-linolenic acid (18:3 n-6) (GLA). Although oils containing GLA, such as Borage oil and Evening Primrose oil (EPO), have been extensively studied for their anti-inflammatory benefits, very little information exists regarding their effects on circulating TG levels. Five studies have been reported in humans in which circulating TGs were monitored following the consumption of oils containing GLA. In all five studies, human diets were supplemented with EPO. Three of the studies showed no effect of the supplementation on circulating TG levels in subjects consuming 0.3 grams, 0.6 grams and 2.7 grams of GLA per day for up to 4 months (Ishikawa, 1989; Abraham, 1990; Viikari 1986). The Abraham study (2.7 grams/day) utilized healthy males without signs of hyperlipidemia, but who were selected based on their being in the lowest quintile for GLA content in adipose tissue biopsies from a larger group of subjects. The Ishikawa study (0.3 grams GLA/day) involved 19 hypercholesterolemic patients. Ten patients did not have associated hypertriglyceridemia and nine were considered hypertriglyceridemic based on a cut off of 150 mg/dL. The Viikari study (0.6 grams GLA/day) utilized hyperlipidemic patients. The two other studies reported that diets supplemented with EPO, delivering either 0.24 grams GLA/day or 2 grams GLA/day, significantly decreased circulating TG levels by 48% and 35%, respectively (Guivernau, 1994; Chaintreuil, 1984). In the Chaintreuil study, all subjects were diabetics taking daily subcutaneous insulin injections. The subjects were grouped to receive either 2 grams GLA/day or 0.5 grams GLA/day. The 2.0 grams/day group were found to have a decrease in plasma TG of 35% while the 0.5 grams/day showed no change in TG levels. The Guivernau paper studied 12 hyperlipidemic men who received 0.24 grams GLA/day. These men had combined hyperlipidemia and any subjects who were taking lipid lowering drugs discontinued the treatment at least 8 weeks before the start of the study. The oil supplement was reported to cause a 48% decrease in plasma TG within a 4 week period, and those individuals with the highest initial levels showed the most marked decrease.
While EPO and Borage Oil are distinctive, in part, because they contain GLA, there have been no reported studies to date which have addressed whether GLA is the active component responsible for the hypotriglyceridemic effects reported in the last-mentioned two studies. Therefore, in view of the inconsistent reports in the literature and the absence of studies addressing whether GLA itself may possess hypotriglyceridemic activity, there is at this time no conclusive evidence to indicate that dietary GLA possesses hypotriglyceridemic properties.
Known pharmaceutical agents for treating hypertriglyceridemia include the class of fibrate drugs, e.g., clofibrate, benzafibrate and gemfibrozil, as well as nicotinic acid and derivatives thereof. Nicotinic acid has been shown to be safe and effective for lowering serum TG levels, but the therapeutic dosage must be worked up to gradually to minimize the flushing and itching of skin which frequently cannot be tolerated by the patient. Clinically relevant interactions of fibrates with other anti-hyperlipidemic drugs include rhabdomyolysis when used in combination with HMG CoA-reductase inhibitors (statins), and decreased bioavailability when combined with certain bile acid sequesterants (Farmer and Gotto, 1994). Also, potentiation of the anticoagulant effects of coumarin may cause bleeding (Blum, 1992).
From the foregoing summary, it will be appreciated that a need exists for a composition for treating hypertriglyceridemia that is both effective and well tolerated by patients to whom it is administrated.
In accordance with one aspect, the present invention provides a composition comprising a mixture of fatty acyl compounds having a polyunsaturated fatty acid content of at least 65 weight percent and including linoleic acid in an amount from about 10 to about 35 weight percent, xcex3-linolenic acid, in an amount from about 5 to about 50 weight percent, xcex1-linolenic acid, in an amount from about 15 to about 60 weight percent and stearidonic acid, in an amount from about 15 to about 55 weight percent, the stated amounts being based on the total weight of the polyunsaturated fatty acid content of the fatty acyl compound mixture, and at least one therapeutic agent selected from the group of antilipemic agents, antioxidants and anti-diabetic agents.
In accordance with another aspect, the present invention provides a method of using the fatty acyl compound mixture described above, with or without the therapeutic agent, for the treatment of hypertriglyceridemia in patients in need of such treatment.
The fatty acyl compound-containing mixture used in the practice of this invention may be formulated from individual fatty acyl compounds, or derived as such from a natural source. As used herein, the expression xe2x80x9cfatty acyl compoundxe2x80x9d refers to various forms of fatty acids, including without limitation, free acids, simple esters, diglycerides, triglycerides, phospholipids, and the like. Phospholipids include, without limitation, lecithins, other fatty acid derivatives of phosphatidic acid, sphingomyelin and plasmalogens. The polyunsaturated fatty acid content of the fatty acyl-compound mixture is determined on the basis of the relative amounts of free acid, when present as such in the mixture, or free acid produced upon hydrolysis of acid derivatives such as esters, di- or triglycerides and phospholipids.
The fatty acyl compound-containing component of the composition is preferably obtained from the seeds of the genus Echium, e.g., Echium plantagineum and Echium vulgaris (hereinafter referred to as Echium oil).
Echium oil contains a unique fatty acyl composition, which upon oral administration to humans results in a significant decrease in circulating triglyceride levels in both normolipidemic as well as in hypotriglyceridemic individuals. Furthermore, for those having predisposition to hypertriglyceridemia, the ingestion of Echium oil reduces the serum level of neutral fat through a daily diet to delay the onset of hypertriglyceridemia.
Echium oil contains important quantities ( greater than 10% each) of four different polyunsaturated fatty acids as set forth in Table 1 below.
Most preferred is the oil obtained from E. Plantagineum, which contains approximately equivalent amounts of GLA, linoleic acid and SDA. Echium oil also has elevated concentrations of ALA (more than double to triple that of other PUFAs). Both ALA and SDA are 18 carbon chain precursors of the long chain n-3 fatty acids found in marine oils.
Oil from E. Plantagineum is commercially available from Croda International PLC of Great Britain. A commercial product can be obtained which is the basic seed extract, having the composition set forth in Table 1 above. Alternatively, a concentrated form of Echium oil may be used, if desired.
As can be seen from the above table, Echium oil also has saturated fatty acid and mono-unsaturated fatty acid components, which predominantly comprise C16 and C18 fatty acids.
There is no other natural oil known which contains the profile of polyunsaturated fatty acids found in Echium oil. Table 2 shows the fatty acyl compositions of the commercially-available oils which most closely approach that of Echium oil.
One of the unusual characteristics of Echium oil is its elevated content of SDA. Black current oil, which has an SDA content of about 4% of the total fatty acids, is the only dietary oil which is anywhere near having the SDA content of Echium oil. SDA is a product of the desaturation of ALA. This desaturation step, which inserts a double bond in the carbon chain, is one of 3 steps required for the conversion of ALA to EPA (which is found in marine oils), as represented below. 
Like ALA, dietary SDA can be converted in tissues to EPA. However, it is not apparent that dietary SDA itself or the conversion of SDA to EPA in tissues will necessarily result in a hypotriglyceridemic effect. Indeed, although individuals who consume ALA show a small increase in tissue levels of EPA, the consumption of up to 20 grams of ALA per day does not result in a lowering of circulating TG levels.
While not wishing to be bound to a particular theory, it is believed that the hypotriglyceridemic effect of dietary Echium oil is likely due to the unique combination of linoleic, GLA, ALA and SDA found in this oil, rather than the individual effect of any one fatty acid component of the oil.
The fatty acyl compound mixture described herein may be used as a complete food product, as a component of a food product, as a dietary supplement or as part of a dietary supplement and may be in either liquid, semisolid or solid form. For example, the fatty acyl compound mixture may be administered as a tablet, a gelatin capsule, a flavored drink, a powder that can be reconstituted into such a drink, a cooking oil, salad oil or dressing, sauce, syrup, mayonnaise, margarine or the like. Preferably, the fatty acyl compound mixture is in the form of a flavored emulsion that can be consumed neat or easily mixed in a drink or yogurt.
The composition of the invention is beneficially administered so as to deliver from about 0.04 to about 0.35 grams of the fatty acyl compound mixture per kilogram of patient body weight per day.
The fatty acyl compound mixture, if desired, may be administered either simultaneously or sequentially in combination with one or more therapeutic agent which has antilipemic, antioxidant or antidiabetic activity. Representative examples of useful of antilipemic agents are nicotinic acid, fluvastatin sodium, cerivastatin sodium, simvastatin, atorvastatin calcium, lovastatin, clofibrate, ciprofibrate, gemfibrozil, benzafibrate, fenofibrate and pravastatin sodium.
Nicotinic acid (niacin) acts by decreasing circulating TGs. The fibrate drugs decrease circulating TGs and LDL-cholesterol. The various statins referred to above block cholesterol synthesis and promote the uptake of LDL-cholesterol by the liver due to an up-regulation of the hepatic LDL receptor. The overall effect produced is a decrease in circulating LDL-cholesterol concentration.
Suitable antioxidants include tocopherol, ascorbic acid, tocotrienol, selenium, curcumin, xcex2-carotene and probucol. These compounds are anti-atherogenic, as they limit the formation of atherogenic oxidized lipoproteins. Antioxidants such as tocopherol, ascorbyl palmitate, ascorbic acid and lecithin or a mixture of such antioxidants also serve to protect the composition against oxidation.
Among the antidiabetic agents which may be incorporated in the composition of this invention are troglitazone, pioglitazone, rosiglitazone and metformin. The glitazone drugs reduce plasma TG, glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus. Metformin lowers moderate (non-diabetic) fasting hypertriglyceridemia in individuals at risk for Type II diabetes.
The composition of the invention may be administered enterally, with oral administration being the preferred route.
Compositions intended for oral administration may be prepared according to any known method for the manufacture of dietary supplements or pharmaceutical preparations, and such compositions may include at least one additive selected from the group consisting of taste improving substances, such as sweetening agents or flavoring agents, stabilizers, emulsifiers, coloring agents and preserving agents in order to provide a dietetically or pharmaceutically palatable preparation. Vitamins, minerals and trace element from any physiologically acceptable source may also be included in the composition of the invention.
In compositions including the above-mentioned therapeutic agents, the dosage and route of administration should be in accordance with the manufacturer""s instructions.
The following examples are provided to illustrate certain embodiments of the invention. They are not intended to limit the invention in any way.